Pharmaceutical aerosol composition containing HFA 227 and HFA 134a

ABSTRACT

In a solution composition for use in an aerosol inhaler which comprises an active material, a propellant containing a hydrofluoroalkane, a cosolvent and optionally a low volatility compound the use of a mixture of HFA 134 a  and HFA 227 allows to modulate the mass median aerodynamic diameter (MMAD) of the aerosol particles on actuation of the inhaler to target specific regions of the respiratory tract. Moreover the fine particle dose (FPD) of the active ingredient in the composition increases by reducing the metering chamber volume.

The invention relates to aerosol compositions for pharmaceutical use. Inparticular, this invention relates to aerosol compositions for use inpressurised metered dose inhalers (MDIs). The invention also relates tosolution aerosol compositions, wherein the propellant comprises HFA 134aor HFA 227 or their mixtures.

Another aspect of the invention relates to pressurised MDIs fordispensing said compositions.

Inhalers are well known devices for administering pharmaceuticalproducts to the respiratory tract by inhalation.

Active materials commonly delivered by inhalation includebronchodilators such as β2 agonists and anticholinergics,corticosteroids, anti-leukotrienes, anti-allergics and other materialsthat may be efficiently administered by inhalation, thus increasing thetherapeutic index and reducing side effects of the active material.

There are a number of types of inhaler currently available. The mostwidely used type is a pressurised metered dose inhaler (MDI) which usesa propellant to expel droplets containing the pharmaceutical product tothe respiratory tract as an aerosol. Formulations used in MDIs (aerosolformulations) generally comprise the active material, one or moreliquefied propellants and a surfactant or a solvent.

For many years the preferred propellants used in aerosols forpharmaceutical use have been a group of chlorofluorocarbons which arecommonly called Freons or CFCs, such as CCl₃F (Freon 11 or CFC-11),CCl₂F₂ (Freon 12 or CFC-12), and CClF₂-CClF₂ (Freon 114 or CFC-114).Chlorofluorocarbons have properties particularly suitable for use inaerosols, including high vapour pressure which generates clouds ofdroplets of a suitable particle size from the inhaler.

Recently, the chlorofluorocarbon (CFC) propellants such as Freon 11 andFreon 12 have been implicated in the destruction of the ozone layer andtheir production is being phased out.

Hydrofluoroalkanes [(HFAs) known also as hydrofluoro-carbons (HFCs)]contain no chlorine and are considered less destructive to ozone andthese are proposed as substitutes for CFCs.

HFAs and in particular 1,1,1,2-tetrafluoroethane (HFA 134a) and1,1,1,2,3,3,3-heptafluoropropane (HFA 227) have been acknowledged to bethe best candidates for non-CFC propellants and a number of medicinalaerosol formulations using such HFA propellant systems are disclosed inseveral patent applications.

Many of these applications, in which HFAs are used as propellant,propose the addition of one or more of adjuvants including compoundsacting as cosolvents, surface active agents including fluorinated andnon-fluorinated surfactants, dispersing agents includingalkylpolyethoxylates and stabilizers.

Cosolvents which may be used in these formulations include alcohols suchas ethanol and polyols such as propylene glycol.

Medicinal aerosol formulations using such propellant systems aredisclosed in, for example, EP 0372777. EP 0372777 requires the use ofHFA 134a as a propellant in combination with both a surfactant and anadjuvant having higher polarity than the propellant.

For aerosol suspension compositions, a surfactant is often added toimprove the physical stability of the suspension. EP 0372777 states thatthe presence of surfactant assists in the preparation of stable,homogeneous suspensions and may also assist in the preparation of stablesolution formulations.

Surfactants also lubricate the valve components in the inhaler device.

The use of propylene glycol as a solvent having a higher polarity thanthe propellant in HFA pressurised metered dose inhalers formulations hasbeen mentioned in several other patent applications and for example in:

EP 504112 relates to a pharmaceutical aerosol formulation free from CFCscontaining a propellant (hydrocarbon, HFA or a mixture), one or morepharmaceutical active ingredients, a non-ionic surfactant and optionallyother conventional pharmaceutical auxiliaries suitable for aerosolformulations comprising solvents having a higher polarity than thepropellant, other non-ionic surfactants as valve lubricants, vegetableoils, phospholipids, taste masking agents.

DE 4123663 describes a medical aerosol composition containing adispersion or suspension of an active agent in association with acompound with surface-active or lipophilic properties,heptafluoropropane as propellant and an alcohol such as ethanol and/orpropylene glycol.

Other applications propose the addition of dispersing agents to thecomposition. U.S. Pat. No. 5,502,076 concerns compositions used ininhalation aerosols comprising an HFA, leukotriene antagonists anddispersing agent comprising 3C-linked triesters, vitamin E acetate,glycerin, t-BuOH, or transesterified oil/polyethylene glycol.

EP 384371, describes a propellant for an aerosol, comprisingpressure-liquefied HFA 227 in a mixture with pressure-liquefied propaneand/or n-butane and/or iso-butane and/or dimethyl ether and/or1,1-difluoroethane. The document also discloses foam formulations(shaving and shower foams) containing glycerol as additive.

The effectiveness of an aerosol device, for example an MDI, is afunction of the dose deposited at the appropriate site in the lungs.Deposition is affected by several parameters, of which the mostimportant are the Fine Particle Dose (FPD) and the aerodynamic particlesize. Solid particles and/or droplets in an aerosol formulation can becharacterized by their mass median aerodynamic diameter (MMAD, thediameter around which the mass aerodynamic diameters are distributedequally)

The FPD gives a direct measure of the mass of particles within aspecified size range and is closely related to the efficacy of theproduct.

Particle deposition in the lung depends largely upon three physicalmechanisms: (1) impaction, a function of particle inertia; (2)sedimentation due to gravity; and (3) diffusion resulting from Brownianmotion of fine, submicrometer (<1 μm) particles. The mass of theparticles determines which of the three main mechanisms predominates.

The effective aerodynamic diameter is a function of the size, shape anddensity of the particles and will affect the magnitude of forces actingon them. For example, while inertial and gravitational effects increasewith increasing particle size and particle density, the displacementsproduced by diffusion decrease. In practice, diffusion plays little partin deposition from pharmaceutical aerosols. Impaction and sedimentationcan be assessed from a measurement of the mass median aerodynamicdiameter (MMAD) which determines the displacement across streamlinesunder the influence of inertia and gravity, respectively.

Aerosol particles of equivalent MMAD and GSD (Geometric StandardDeviation) have similar deposition in the lung irrespective of theircomposition. The GSD is a measure of the variability of the aerodynamicparticle diameters.

For inhalation therapy there is a preference for aerosols in which theparticles for inhalation have a diameter of about 0.8 to 5 μm. Particleswhich are larger than 5 μm in diameter are primarily deposited byinertial impaction in the oropharynx, particles 0.5 to 5 μm in diameter,influenced mainly by gravity, are ideal for deposition in the conductingairways, and particles 0.5 to 3 μm in diameter are desirable for aerosoldelivery to the lung periphery. Particles smaller than 0.5 μm may beexhaled.

Respirable particles are generally considered to be those withaerodynamic diameters less than 5 μm. These particles, particularlythose with a diameter of about 3 μm, are efficiently deposited in thelower respiratory tract by sedimentation.

Besides the therapeutic purposes, the size of aerosol particles isimportant in respect to the side effects of the drugs. For example, itis well known that the oropharynx deposition of aerosol formulations ofsteroids can result in side effects such as candidiasis of mouth andthroat.

On the other hand a higher systemic exposure to the aerosol particlesdue to deep lung penetration can enhance the undesired systemic effectsof the drugs. For example, the systemic exposure to steroids can produceside effects on bone metabolism and growth.

It has been reported that the particle size characteristics of HFAaerosol formulations of the state of the art are often very differentfrom the products to be replaced.

HFA substitutes may not be pharmaceutically or clinically equivalent andadjustment of dose and regimen may be necessary, giving problems fordoctor, pharmacist and patient.

An alternative is the seamless transition from the old to the newformulas which demands the same deposition of the drug in the lung. Forany product, this can be inferred from the amount of drug and itsparticle size distribution in the aerosol cloud. Matching CFC and HFAformulations with suspension technology is practicable because theparticle size of the aerosol cloud is dominated by the particle size ofthe suspended drug, defined by the milling or precipitation process.

However, when, as commonly occurs, solution formulations areunavoidable, the volumetric contribution of suspended particles isabsent and much finer clouds, largely defined by the concentration ofthe drug in the solution, are generated. In these circumstances, acosolvent, such as alcohol, is often added to ensure satisfactorysolubility. The fine clouds from such formulations give more extensivedeposition in the lung periphery than their CFC counterparts.

EP 0553298 describes an aerosol formulation comprising: atherapeutically effective amount of beclomethasone 17,21 dipropionate(BDP); a propellant comprising a hydrofluorocarbon selected from thegroup consisting of HFA 134a, HFA 227, and a mixture thereof, andethanol in an amount effective to solubilize the beclomethasone 17,21dipropionate in the propellant. The formulation is further characterizedin that substantially all of the beclomethasone 17,21 dipropionate isdissolved in the formulation and that the formulation contains no morethan 0,0005% by weight of any surfactant.

It has been reported in literature that these new formulations ofbeclomethasone dipropionate (BDP) as a solution in HFA 134a deliver aparticle size distribution with a MMAD of 1.1 μm. This means that theperipheral pulmonary deposition of very small particles increases andsubmicronic particles can easily be directly absorbed from the alveoliinto the bloodstream. The rate and extent of systemic absorption issignificantly increased and as a consequence undesired effects forexample certain side effects can increase. A relatively large fractionof the dose is exhaled. The implications of this for clinical efficacyand toxic effects are great. They arise because the principles offormulation using HFAs may modify the physical form of the respiredcloud.

It has now been surprisingly found that in solution formulations of thepresent application comprising an active material, a propellantcontaining a hydrofluoroalkane (HFA), a cosolvent and optionally a lowvolatility compound, the use of a mixture of HFA 134a and of HFA 227allows the modulation of the MMAD of the aerosol particles on actuationof the inhaler to a value which is suited for the pulmonaryadministration.

Mixtures of hydrofluoroalkanes have been previously used insuspension-based pMDI compositions to vary the density of the continuousphase in order to match the density of the suspended drug and maximizethe physical stability of the pMDI suspension.

Williams R. O. et al. in Drug Dev. Ind. Pharm. 24 (8), 763-770, 1998investigated the influence of propellant composition on thecharacteristics of suspension aerosol compositions. The results showedthat as the density of the propellant blends approached the density ofthe suspended drug particles, the formulation became more physicallystable.

Analogously, WO93/11747 discloses that in suspension aerosolcompositions the density of the propellant may be changed by using HFA134a and HFA 227 mixtures so as to bring it to approximately the samevalue of the density of the active ingredient, minimizing thereby thesedimentation of the drug particles.

Therefore the aerosol compositions using the new propellant systemsdisclosed in the known prior art seek to overcome problems of physicalstability of the formulations.

It has surprisingly been found that in solution compositions by using amixture of HFA 134a and HFA 227 and optionally a low volatilitycomponent, the MMAD of the aerosol particles on actuation of the inhalercan be modulated and thus the compositions may be formulated so that theaerodynamic particle size characteristics are optimized.

Advantageously, the low volatility component has a vapour pressure at25° C. not more than 0.1 kPa, preferably not more than 0.05 kPa.

The low vapour pressure of the low volatility component is to becontrasted with that of the cosolvent which preferably has a vapourpressure at 25° C. not less than 3 kPa, more preferably not less than 5kPa.

The cosolvent has advantageously a higher polarity than that of thepropellant and the cosolvent is used to increase the solubility of theactive material in the propellant.

Advantageously the cosolvent is an alcohol. The cosolvent is preferablyethanol. The cosolvent may include one or more materials.

The low volatility component may be a single material or a mixture oftwo or more materials.

In general terms the low volatility component can be any compound, safeand compatible with the propellant system of the invention capable toinfluence either the size or the density of the aerosol particle soaffecting the MMAD.

We have found that glycols are particularly suitable for use as the lowvolatility component, especially propylene glycol, polyethylene glycoland glycerol.

Other particularly suitable materials are thought to include otheralcohols and glycols, for example alkanols such as decanol (decylalcohol), sugar alcohols including sorbitol, mannitol, lactitol andmaltitol, glycofural (tetrahydro-furfurylalcohol) and dipropyleneglycol.

The low volatility component may include esters for example ascorbylpalmitate and tocopherol. Among the esters isopropyl myristate isparticularly preferred.

It is also envisaged that various other materials may be suitable foruse as the low volatility component including vegetable oils, organicacids for example saturated carboxylic acids including lauric acid,myristic acid and stearic acid; unsaturated carboxylic acids includingsorbic acid, and especially oleic acid, which has been previously usedin aerosol formulations, in order to improve the physical stability ofdrug suspensions, as a dispersing agent useful in keeping the suspendedparticles from agglomerating; saccharine, ascorbic acid, cyclamic acid,amino acids or aspartame; alkanes for example dodecane and octadecane;terpenes for example menthol, eucalyptol, limonene; sugars for examplelactose, glucose, sucrose; polysaccharides for example ethyl cellulose,dextran; antioxidants for example butylated hydroxytoluene, butylatedhydroxyanisole; polymeric materials for example polyvinyl alcohol,polyvinyl acetate, polyvinyl pyrollidone; amines for exampleethanolamine, diethanolamine, triethanolamine; steroids for examplecholesterol, cholesterol esters.

The amount of low volatility component in the composition depends tosome extent upon its density and the amount of active material andcosolvent in the composition. Advantageously, the composition includesnot more than 20% by weight of the low volatility component. Preferablythe composition includes not more than 10% by weight of the lowvolatility component.

On actuation of the inhaler, the propellant and the ethanol vaporise butbecause of the low vapour pressure of the low volatility component, thatcomponent generally will not.

It is thought that it is preferable for the composition to contain atleast 0.2%, preferably at least 1% by weight of the low volatilitycomponent. The composition may contain between 1% and 2% by weight.

According to the present invention, as it can be noticed from theresults reported in the tables, the influence on the MMAD of theparticles is correlated to the ratio of the two HFA components (as wellas to the amount and density of the low volatility component).

The MMAD can be modulated by changing the ratio between HFA 134a and HFA227; said ratio may range from 10:90 to 90:10.

From the data reported in Table 1, it is clear that MMAD is increased byincreasing the proportion of HFA 227 in the mixture.

Most advantageously, the composition is such that, on actuation of theaerosol inhaler in use, the MMAD of the aerosol particles is not lessthan 2 μm. For some active materials the MMAD is preferably not lessthan 2.5 μm and for a few formulations, the preferred MMAD will begreater than 3 μm or even greater than 4 μm.

In some cases a small quantity of water may be added to the compositionto improve the solution of the active material and/or the low volatilitycomponent in the cosolvent.

The active material may be one or more of any biologically activematerial which could be administered by inhalation. Active materialscommonly administered in that way include β2 agonists, for examplesalbutamol and its salts, steroids for example beclomethasonedipropionate or anti-cholinergics for example ipratropium bromide andcombinations thereof.

As indicated above, on actuation of the inhaler, the aerosol particlesadvantageously have an MMAD of not less than 2 μm, for many formulationsmore preferably not less than 2.5 μm.

It has also been found, and it is a further object of the invention,that it is possible to increase the “fine particle dose” or FPD of theactive ingredients in the compositions of the invention, withoutaffecting MMAD, by decreasing the metering chamber volume of the metereddose inhaler (increasing thereby the space above it named “sump”) and/orchanging the ratio between the metering chamber and the space above byincreasing the sump. In particular, by reducing the metering chambervolume from 50 μl to 25 μl at sump volume constant, it is possible toincrease the fine particle delivery up to 40%.

This result could be only obtained with solution compositions in whichthe MMAD of the particles is higher than 2 μm and it is particularlysurprising since it is known from Williams R. O. et al. inPharmaceutical Research 14 (4), 438-443, 1997 that in suspension basedpMDI containing HFA 134a the aerodynamic particle size distribution wasnot influenced as the metering chamber volume of the valve wasincreased.

The solution formulations with MMAD>2 may be obtained by using ametering chamber <40 μl, preferably 25 μl: the fine particle delivery(Stage 3 to filter; <4.7 μm) determined through a Andersen CascadeImpactor is increased by at least 10% in comparison with the sameformulation packaged with a valve with a metering chamber of at least 50μl and the same sump, as it will be shown hereinbelow.

Using a reduced metering chamber volume (e.g. about 40 μl or lower for aconventional inhaler), favourable results are obtained even with aerosolcompositions wherein the propellant consists either in HFA 227 or in HFA134a alone.

Also provided is a method of filling an aerosol inhaler with acomposition, the method comprising filling the following components intothe inhaler

(a) one or more active materials,

(b) optionally one or more low volatility components,

(c) one or more cosolvents followed by the addition of a propellantcontaining a hydrofluoroalkane (HFA) or a mixture of HFAs.

Embodiments of the invention will now be described by way of example.

The aerosol compositions of the invention described below were preparedby the following method. The required components of a composition wereadded into a can in the following order: drug, non-volatile additive,absolute ethanol. After crimping of the valve on to the can, thepropellant was added through the valve. The weight gain of the can aftereach component was added was recorded to allow the percentage, byweight, of each component in the formulation to be calculated.

The aerodynamic particle size distribution of each formulation wascharacterized using a Multistage Cascade Impactor according to theprocedure described in the European Pharmacopoeia 2nd edition, 1995,part V.5.9.1. pages 15-17. In this specific case an Andersen CascadeImpactor (ACI) was used. Results represented were obtained from tencumulative actuations of a formulation. Deposition of the drug on eachACI plate was determined by high pressure liquid chromatography. Themass median aerodynamic diameter (MMAD) and geometric standard deviation(GSD) were calculated from plots of the cumulative percentage undersizeof drug collected on each ACI plate (probit scale), against the uppercut off diameter for each respective ACI plate (log10 scale). The fineparticle dose of each formulation was determined from the mass of drugcollected on Stages 3 through to Filter (<4.7 μm) divided by the numberof actuations per experiment.

Table 1 shows the MMAD characteristics of aerosol formulationscontaining beclomethasone dipropionate (BDP) (active material), glycerolas low volatility component and different mixtures of HFA 134a and HFA227. As can be seen, the MMAD is substantially influenced by the ratioof the two fluorocarbons whereas FPD is substantially unaffected.

The presence of the low volatility component contributes to themodulation of the MMAD: its percent content (w/w) can be properlyadapted to obtain the desired MMAD.

Table 2 shows the effects of valve chamber (also known as meteringchamber) volumes at sump volume constant on the generation of aerosolclouds.

In particular, the data shown in Table 2 show that FPD increases withdecreasing valve chamber volume and that FPD can be increased by morethat 40% by reducing the volume of a valve metering chamber. MMAD or GSDare not conversely affected by changing the volume of the valve-meteringchamber.

Therefore, the compositions of the invention consisting of aerosol drugsolution in a mixture of 134a and 227 HFA propellants, a cosolvent andoptionally a low volatility component, added into an aerosol inhalerhaving a chamber volume ranging from 25 to 50 μl, constitute a deliverysystem which allow improvement of the delivery characteristics of drugsto the lung by modulating the aerodynamic particle size and sizedistribution so that the pattern of deposition gives the desiredclinical effect.

To obviate possible chemical stability problems of active ingredients insolution in HFA propellants metered-dose inhalers having part or all oftheir internal metallic surfaces consisting of stainless steel, anodizedaluminium or lined with an inert organic coating can be employed.

TABLE 1 Effect of HFA 134a/HFA 227 mixtures upon the MMAD of pMDIsolution formulation BDP 250 μg/shot Ethanol 15% (w/w) Glycerol 1.3%(w/w) HFA to 12 ml Actuator = 0.30 mm HFA 227/ MMAD FPD FPD₃ < 4.7 μm*HFA 134a (μm) (%) (μg) 100:0  4.2, 3.9, 3.8 20, 20, 24 47, 45, 50 75:253.7, 3.7 25, 25 56, 57 50:50 3.4, 3.7 25, 25 56, 56 25:75 3.3, 3.2 27,28 60, 62  0:100 2.8, 2.8 27, 27 58, 59 *Results normalized for 250nominal dose.

TABLE 2 Effect of Valve Chamber Volume upon the FPD of pMDIs containingHFA 134a and HFA 227 Solutions Formulations BDP 50 μg/shot Ethanol 13%(w/w) Glycerol 1.3% (w/w) HFA to 12 ml Chamber Metered Volume FPD < 4.7μm MMAD Dose (μl) Propellant (μg) (μm) GSD (μg) actuator orifice 0.30 mm 25 HFA 134a 19.2 2.6 2.0 57  50 13.9 2.8 2.1 49 100 11.7 2.7 2.2 51  25HFA 227 16.4 3.6 2.1 58  50 13.1 3.5 2.2 51 100 12.6 3.5 2.2 49 actuatororifice 0.25 mm  25 HFA 134a 26.0 2.8 1.9 55

What is claimed is:
 1. A composition in the form of a solutioncomprising: a solubilized active material, a propellant comprising HFA227 and HFA 134a, and optionally, a low volatility component, or acosolvent, or both, wherein the ratio of HFA 227: HFA 134a ranges from10:90 to 90:10 and the active material is an anticholinergic drug, acorticosteroid, or a β2 agonist.
 2. The composition according to claim1, wherein the low volatility component has a vapour pressure at 25° C.lower than 0.1 kPa.
 3. The composition according to claim 1, wherein thelow volatility component has a vapour pressure at 25° C. lower than 0.05kPa.
 4. The composition according to claim 1, wherein the cosolvent hasa vapour pressure at 25° C. lower than 3 kPa.
 5. The compositionaccording to claim 1, wherein the cosolvent has a vapour pressure at 25°C. lower than 5 kPa.
 6. The composition according to claim 1, whereinthe cosolvent is an alcohol.
 7. The composition according to claim 1,wherein the low volatility component includes a glycol, oleic acid orisopropyl myristate.
 8. The composition according to claim 1, whereinthe composition comprises not more than 20% by weight of the lowvolatility component.
 9. The composition according to claim 1 comprisingat least 0.2% by weight of the low volatility component.
 10. An aerosolinhaler comprising a composition in the form of a solution wherein saidsolution comprises an active material, a propellant containing one ormore hydrofluoroalkane(s), a cosolvent and optionally a low volatilitycomponent, wherein the particle MMAD produced by said aerosol inhaler isgreater than 2 μm and the fine particle dose (<4.7 μm) is >30%, with theproviso that the active material is not Cyclosporin A.
 11. An aerosolinhaler according to claim 10 that produces a particle MMAD greater than2 μm and a fine particle dose (<4.7 μm) of >40%.
 12. An aerosol inhaleraccording to claim 10 that produces a particle MMAD greater than 2 μmand a fine particle dose (<4.7 μm) of >50%.
 13. The aerosol inhaleraccording to claim 10 having a chamber volume ranging from 25 to 40 μlyielding an increase of FPD compared to inhalers having chamber volumeslarger than 50 μl.
 14. The aerosol inhaler according to claim 10,wherein part or all of the internal surface(s) comprise stainless steel,anodized aluminium or an inert organic coating.
 15. A delivery systemfor the administration of one or more drugs to the lung consisting ofaerosol drug solution in a mixture of 134a and 227 HFA propellants, acosolvent and optionally a low volatility component, in an aerosolinhaler having a chamber volume ranging from 25 to 40 μm, wherein theMMAD of the aerosol particles on actuation of the inhaler is not lessthan 2 μm and the fine particle dose (<4.7 μm) is at least 30%.
 16. Adelivery system comprising the composition of claim
 1. 17. The deliverysystem of claim 16 that produces an aerosol comprising particles havinga mass median aerodynamic diameter (MMAD) not less than 2 μm.
 18. Anaerosol inhaler comprising the composition of claim
 1. 19. The aerosolinhaler of claim 18 that is a metered dose inhaler.
 20. The aerosolinhaler of claim 18 that produces an aerosol comprising particles havinga mass median aerodynamic diameter (MMAD) not less than 2 μm.
 21. Thecomposition of claim 1, wherein the active material comprises a β2agonist.
 22. The composition of claim 1, wherein the active materialcomprises a corticosteroid.
 23. The composition of claim 1, wherein theactive material comprises an anti-cholinergic drug.
 24. The compositionof claim 1 in the form of an aerosol.
 25. An aerosol produced from thecomposition of claim 1 by a delivery system.
 26. The aerosol of claim 25that comprises particles having a mass median aerodynamic diameter(MMAD) not less than 2 μm.
 27. The composition of claim 24, wherein theactive material comprises an anticholinergic drug.
 28. The compositionof claim 24, wherein the active material comprises a β2 agonist.
 29. Thecomposition of claim 24, wherein the active material comprises acorticosteroid.